ES2305844T3 - Derivados de quinazolina como inhibidores de tirosina cinasa. - Google Patents
Derivados de quinazolina como inhibidores de tirosina cinasa. Download PDFInfo
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- ES2305844T3 ES2305844T3 ES04768469T ES04768469T ES2305844T3 ES 2305844 T3 ES2305844 T3 ES 2305844T3 ES 04768469 T ES04768469 T ES 04768469T ES 04768469 T ES04768469 T ES 04768469T ES 2305844 T3 ES2305844 T3 ES 2305844T3
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- Prior art keywords
- alkyl
- group
- formula
- amino
- alkoxy
- Prior art date
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title claims description 28
- 239000003112 inhibitor Substances 0.000 title description 19
- 108091000080 Phosphotransferase Proteins 0.000 title description 12
- 102000020233 phosphotransferase Human genes 0.000 title description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 391
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 354
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 250
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 170
- 125000001424 substituent group Chemical group 0.000 claims abstract description 116
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 101
- 150000002367 halogens Chemical class 0.000 claims abstract description 52
- 239000001257 hydrogen Substances 0.000 claims abstract description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 50
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 45
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 39
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 38
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 25
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 23
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 22
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 22
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 22
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 12
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 claims abstract description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 10
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 9
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000001589 carboacyl group Chemical group 0.000 claims abstract 15
- 238000000034 method Methods 0.000 claims description 144
- 150000001875 compounds Chemical class 0.000 claims description 143
- 150000003839 salts Chemical class 0.000 claims description 115
- 150000003246 quinazolines Chemical class 0.000 claims description 113
- 150000002148 esters Chemical class 0.000 claims description 88
- 238000006243 chemical reaction Methods 0.000 claims description 83
- 206010028980 Neoplasm Diseases 0.000 claims description 48
- 239000002253 acid Substances 0.000 claims description 43
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 41
- 238000011282 treatment Methods 0.000 claims description 36
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 34
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 34
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 33
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 33
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 30
- 125000006239 protecting group Chemical group 0.000 claims description 30
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 30
- 238000005859 coupling reaction Methods 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 28
- 201000011510 cancer Diseases 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 241000282414 Homo sapiens Species 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 24
- 230000005764 inhibitory process Effects 0.000 claims description 22
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 22
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 21
- 150000001721 carbon Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 19
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 19
- 239000000460 chlorine Chemical group 0.000 claims description 19
- 229910052801 chlorine Chemical group 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 19
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 19
- 229910005965 SO 2 Inorganic materials 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 claims description 17
- 125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 17
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 17
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 17
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 125000000524 functional group Chemical group 0.000 claims description 14
- 125000002757 morpholinyl group Chemical group 0.000 claims description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 13
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 230000035755 proliferation Effects 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 11
- 238000010168 coupling process Methods 0.000 claims description 11
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 11
- 210000004881 tumor cell Anatomy 0.000 claims description 11
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 10
- 230000001028 anti-proliverative effect Effects 0.000 claims description 10
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 10
- 125000003551 oxepanyl group Chemical group 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 230000019491 signal transduction Effects 0.000 claims description 9
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- HKPQKTRFULBKRH-ZDUSSCGKSA-N (2s)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@H](C)O)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F HKPQKTRFULBKRH-ZDUSSCGKSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- HVAFDEWTWXYBEI-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxyethanone Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)CO)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F HVAFDEWTWXYBEI-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 238000003776 cleavage reaction Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- NJAVGTVVSVDFBS-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-ethoxyethanone Chemical compound C1CN(C(=O)COCC)CCC1OC1=CC2=NC=NC(NC=3C(=C(Cl)C=CC=3)F)=C2C=C1OC NJAVGTVVSVDFBS-UHFFFAOYSA-N 0.000 claims description 5
- ZGMRFKHEJQIHAC-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-methoxyethanone Chemical compound C1CN(C(=O)COC)CCC1OC1=CC2=NC=NC(NC=3C(=C(Cl)C=CC=3)F)=C2C=C1OC ZGMRFKHEJQIHAC-UHFFFAOYSA-N 0.000 claims description 5
- NBVMYRZKSWXDGP-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-3-hydroxy-2,2-dimethylpropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)C(C)(C)CO)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F NBVMYRZKSWXDGP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 125000005724 cycloalkenylene group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000003780 insertion Methods 0.000 claims description 4
- 230000037431 insertion Effects 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- GZLIERPQHXYFPW-CQSZACIVSA-N (2r)-1-[4-[4-(3-bromoanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@@H](C)O)C(OC)=CC2=C1NC1=CC=CC(Br)=C1 GZLIERPQHXYFPW-CQSZACIVSA-N 0.000 claims description 3
- CQMVEBHVXXRLHJ-HXUWFJFHSA-N (2r)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-(dimethylamino)-3-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@@H](CO)N(C)C)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F CQMVEBHVXXRLHJ-HXUWFJFHSA-N 0.000 claims description 3
- HKPQKTRFULBKRH-CYBMUJFWSA-N (2r)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@@H](C)O)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F HKPQKTRFULBKRH-CYBMUJFWSA-N 0.000 claims description 3
- GKAQAIGUPWXDDZ-CQSZACIVSA-N (2r)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-methoxypropan-1-one Chemical compound C1CN(C(=O)[C@@H](C)OC)CCC1OC1=CC2=NC=NC(NC=3C(=C(Cl)C=CC=3)F)=C2C=C1OC GKAQAIGUPWXDDZ-CQSZACIVSA-N 0.000 claims description 3
- HAKPDIYCVPGVFD-ZDUSSCGKSA-N (2s)-1-[4-[4-(3-bromo-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@H](C)O)C(OC)=CC2=C1NC1=CC=CC(Br)=C1F HAKPDIYCVPGVFD-ZDUSSCGKSA-N 0.000 claims description 3
- GZLIERPQHXYFPW-AWEZNQCLSA-N (2s)-1-[4-[4-(3-bromoanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@H](C)O)C(OC)=CC2=C1NC1=CC=CC(Br)=C1 GZLIERPQHXYFPW-AWEZNQCLSA-N 0.000 claims description 3
- OMWBEABLDPYCPY-HSZRJFAPSA-N (2s)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxy-3,3-dimethylbutan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@@H](O)C(C)(C)C)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F OMWBEABLDPYCPY-HSZRJFAPSA-N 0.000 claims description 3
- GKAQAIGUPWXDDZ-AWEZNQCLSA-N (2s)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-methoxypropan-1-one Chemical compound C1CN(C(=O)[C@H](C)OC)CCC1OC1=CC2=NC=NC(NC=3C(=C(Cl)C=CC=3)F)=C2C=C1OC GKAQAIGUPWXDDZ-AWEZNQCLSA-N 0.000 claims description 3
- BULJPQYHBWJOTR-OWJWWREXSA-N (2s,3s)-1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-hydroxy-3-methylpentan-1-one Chemical compound C1CN(C(=O)[C@@H](O)[C@@H](C)CC)CCC1OC1=CC2=NC=NC(NC=3C(=C(Cl)C=CC=3)F)=C2C=C1OC BULJPQYHBWJOTR-OWJWWREXSA-N 0.000 claims description 3
- BBWHNPBFCSESKS-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-(2-methoxyethoxy)ethanone Chemical compound C1CN(C(=O)COCCOC)CCC1OC1=CC2=NC=NC(NC=3C(=C(Cl)C=CC=3)F)=C2C=C1OC BBWHNPBFCSESKS-UHFFFAOYSA-N 0.000 claims description 3
- PZZCHOWGOUUGLJ-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-(4-methylpiperazin-1-yl)ethanone Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)CN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F PZZCHOWGOUUGLJ-UHFFFAOYSA-N 0.000 claims description 3
- MZVZZNYVRCEGDS-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)CN(C)C)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F MZVZZNYVRCEGDS-UHFFFAOYSA-N 0.000 claims description 3
- POPHFBPAYSUVDB-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-3-hydroxy-3-methylbutan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)CC(C)(C)O)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F POPHFBPAYSUVDB-UHFFFAOYSA-N 0.000 claims description 3
- ZWEKFSQMEWHVMO-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-3-hydroxypropan-1-one Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)CCO)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F ZWEKFSQMEWHVMO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 3
- QEZHNZSLNKRLMM-FQEVSTJZSA-N [4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-[(2s)-oxolan-2-yl]methanone Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)[C@H]3OCCC3)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F QEZHNZSLNKRLMM-FQEVSTJZSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- QEZHNZSLNKRLMM-UHFFFAOYSA-N [4-[4-(3-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]-(oxolan-2-yl)methanone Chemical compound N1=CN=C2C=C(OC3CCN(CC3)C(=O)C3OCCC3)C(OC)=CC2=C1NC1=CC=CC(Cl)=C1F QEZHNZSLNKRLMM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229940127557 pharmaceutical product Drugs 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 15
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 74
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 185
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 122
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 85
- 238000001819 mass spectrum Methods 0.000 description 79
- 239000000243 solution Substances 0.000 description 68
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 66
- 239000000047 product Substances 0.000 description 64
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- 239000007787 solid Substances 0.000 description 55
- 125000002252 acyl group Chemical group 0.000 description 53
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 46
- 239000000203 mixture Substances 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000006260 foam Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000007858 starting material Substances 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000003818 flash chromatography Methods 0.000 description 27
- 102000001301 EGF receptor Human genes 0.000 description 26
- 108060006698 EGF receptor Proteins 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- 239000002585 base Substances 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 20
- 239000000843 powder Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 17
- 239000002953 phosphate buffered saline Substances 0.000 description 17
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Classifications
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- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
- C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
- C04B35/632—Organic additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0321620 | 2003-09-16 | ||
| GBGB0321620.7A GB0321620D0 (en) | 2003-09-16 | 2003-09-16 | Quinazoline derivatives |
| GB0406163A GB0406163D0 (en) | 2004-03-19 | 2004-03-19 | Quinazoline derivatives |
| GB0406163 | 2004-03-19 |
Publications (1)
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| ES2305844T3 true ES2305844T3 (es) | 2008-11-01 |
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| ES04768469T Active ES2305844T3 (es) | 2003-09-16 | 2004-09-13 | Derivados de quinazolina como inhibidores de tirosina cinasa. |
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| ATE423104T1 (de) * | 2001-11-03 | 2009-03-15 | Astrazeneca Ab | Quinazolin derivate als antitumor-mittel |
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| BRPI0414488A (pt) * | 2003-09-16 | 2006-11-14 | Astrazeneca Ab | derivado de quinazolina, composição farmacêutica, uso de um derivado de quinazolina, métodos para produzir um efeito anti - proliferativo em um animal de sangue quente, para prevenção ou tratamento de tumores em um aminal de sangue quente, para fornecer um efeito inibidor da tirosina quinase de egfr seletivo em um animal de sangue quente e para tratar um cáncer em um animal de sangue quente e, processo para a preparação de um derivado de quinazolina |
| GB0321648D0 (en) * | 2003-09-16 | 2003-10-15 | Astrazeneca Ab | Quinazoline derivatives |
| US20080234263A1 (en) * | 2003-09-16 | 2008-09-25 | Laurent Francois Andre Hennequin | Quinazoline Derivatives |
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| GB0326459D0 (en) * | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
| US20080113874A1 (en) * | 2004-01-23 | 2008-05-15 | The Regents Of The University Of Colorado | Gefitinib sensitivity-related gene expression and products and methods related thereto |
| WO2005070020A2 (en) * | 2004-01-23 | 2005-08-04 | The Regents Of The University Of Colorado | Gefitinib sensitivity-related gene expression and products and methods related thereto |
| WO2005075439A1 (en) * | 2004-02-03 | 2005-08-18 | Astrazeneca Ab | Quinazoline derivatives |
| CA2567293C (en) * | 2004-05-27 | 2017-05-16 | The Regents Of The University Of Colorado | Methods for prediction of clinical outcome to epidermal growth factor receptor inhibitors by cancer patients |
| MXPA06014125A (es) * | 2004-06-04 | 2007-01-31 | Astrazeneca Ab | Derivados de quinazolina en la forma de cinasas de tirosina de receptor erbb. |
| WO2006044687A2 (en) | 2004-10-15 | 2006-04-27 | Takeda San Diego, Inc. | Kinase inhibitors |
| JP4881875B2 (ja) * | 2004-12-14 | 2012-02-22 | アストラゼネカ アクチボラグ | 抗腫瘍剤としてのピラゾロピリミジン化合物 |
| GB0504474D0 (en) * | 2005-03-04 | 2005-04-13 | Astrazeneca Ab | Chemical compounds |
| JP2008533053A (ja) * | 2005-03-11 | 2008-08-21 | ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド | ヒストン脱アセチル化酵素阻害剤は、がん細胞を上皮増殖因子受容体阻害剤に対して感受性にする |
| GB0508717D0 (en) * | 2005-04-29 | 2005-06-08 | Astrazeneca Ab | Chemical compounds |
| GB0508715D0 (en) * | 2005-04-29 | 2005-06-08 | Astrazeneca Ab | Chemical compounds |
| WO2007023073A2 (de) * | 2005-08-22 | 2007-03-01 | Boehringer Ingelheim International Gmbh | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
| WO2007034144A1 (en) * | 2005-09-20 | 2007-03-29 | Astrazeneca Ab | 4- (ih-indazol-s-yl-amino)-quinazoline compounds as erbb receptor tyrosine kinase inhibitors for the treatment of cancer |
| EP1940825A1 (en) * | 2005-09-20 | 2008-07-09 | Astra Zeneca AB | Quinazoline derivatives as anticancer agents |
| US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| WO2007063293A1 (en) * | 2005-12-02 | 2007-06-07 | Astrazeneca Ab | Quinazoleine derivatives used as inhibitors of erbb tyrosine kinase |
| WO2007063291A1 (en) * | 2005-12-02 | 2007-06-07 | Astrazeneca Ab | 4-anilino-substituted quinazoline derivatives as tyrosine kinase inhibitors |
| US7547781B2 (en) | 2006-09-11 | 2009-06-16 | Curis, Inc. | Quinazoline based EGFR inhibitors containing a zinc binding moiety |
| KR20090067169A (ko) | 2006-09-11 | 2009-06-24 | 쿠리스 인코퍼레이션 | 아연 결합 부분을 함유한 퀴나졸린 계열 ｅｇｆｒ 억제제 |
| SG158147A1 (en) | 2006-10-09 | 2010-01-29 | Takeda Pharmaceutical | Kinase inhibitors |
| CA2723989C (en) | 2008-05-13 | 2017-04-25 | Astrazeneca Ab | Fumarate salt of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline |
| CN102452988B (zh) | 2010-10-27 | 2016-01-27 | 中国科学院化学研究所 | 一种喹唑啉衍生物及其制备方法 |
| AU2012225735B2 (en) | 2011-03-04 | 2016-03-10 | Glaxosmithkline Intellectual Property Development Limited | Amino-quinolines as kinase inhibitors |
| TWI547494B (zh) | 2011-08-18 | 2016-09-01 | 葛蘭素史克智慧財產發展有限公司 | 作為激酶抑制劑之胺基喹唑啉類 |
| TW201425307A (zh) | 2012-09-13 | 2014-07-01 | Glaxosmithkline Llc | 作為激酶抑制劑之胺基－喹啉類 |
| AR092529A1 (es) | 2012-09-13 | 2015-04-22 | Glaxosmithkline Llc | Compuesto de aminoquinazolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento |
| AU2014220300B2 (en) | 2013-02-21 | 2016-10-13 | Glaxosmithkline Intellectual Property Development Limited | Quinazolines as kinase inhibitors |
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-
2004
- 2004-09-13 JP JP2006526682A patent/JP4795952B2/ja not_active Expired - Fee Related
- 2004-09-13 RU RU2006112599/04A patent/RU2378268C2/ru not_active IP Right Cessation
- 2004-09-13 SI SI200430769T patent/SI1667991T1/sl unknown
- 2004-09-13 MX MXPA06002964A patent/MXPA06002964A/es active IP Right Grant
- 2004-09-13 WO PCT/GB2004/003923 patent/WO2005026150A1/en active IP Right Grant
- 2004-09-13 UA UAA200604148A patent/UA84167C2/ru unknown
- 2004-09-13 BR BRPI0414489A patent/BRPI0414489A8/pt not_active Application Discontinuation
- 2004-09-13 PL PL04768469T patent/PL1667991T3/pl unknown
- 2004-09-13 AU AU2004272348A patent/AU2004272348B2/en not_active Ceased
- 2004-09-13 AT AT04768469T patent/ATE395346T1/de not_active IP Right Cessation
- 2004-09-13 US US10/573,090 patent/US7569577B2/en not_active Expired - Fee Related
- 2004-09-13 DE DE602004013806T patent/DE602004013806D1/de active Active
- 2004-09-13 CA CA2538884A patent/CA2538884C/en not_active Expired - Fee Related
- 2004-09-13 PT PT04768469T patent/PT1667991E/pt unknown
- 2004-09-13 ES ES04768469T patent/ES2305844T3/es active Active
- 2004-09-13 DK DK04768469T patent/DK1667991T3/da active
- 2004-09-13 EP EP04768469A patent/EP1667991B1/en active Active
- 2004-09-14 TW TW093127785A patent/TW200519104A/zh unknown
- 2004-09-16 AR ARP040103321A patent/AR045663A1/es not_active Application Discontinuation
-
2006
- 2006-03-12 IL IL174261A patent/IL174261A0/en unknown
- 2006-03-23 NO NO20061322A patent/NO20061322L/no not_active Application Discontinuation
- 2006-04-10 CO CO06034940A patent/CO5690594A2/es not_active Application Discontinuation
- 2006-10-31 HK HK06111949A patent/HK1091480A1/xx not_active IP Right Cessation
-
2008
- 2008-07-07 HR HR20080329T patent/HRP20080329T3/xx unknown
- 2008-07-10 CY CY20081100724T patent/CY1108186T1/el unknown
-
2009
- 2009-06-11 US US12/482,620 patent/US20090312343A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0414489A (pt) | 2006-11-14 |
| CA2538884C (en) | 2010-09-21 |
| EP1667991B1 (en) | 2008-05-14 |
| PL1667991T3 (pl) | 2008-12-31 |
| US7569577B2 (en) | 2009-08-04 |
| EP1667991A1 (en) | 2006-06-14 |
| BRPI0414489A8 (pt) | 2019-01-15 |
| IL174261A0 (en) | 2006-08-01 |
| US20070043009A1 (en) | 2007-02-22 |
| TW200519104A (en) | 2005-06-16 |
| AU2004272348A1 (en) | 2005-03-24 |
| HRP20080329T3 (en) | 2008-08-31 |
| UA84167C2 (ru) | 2008-09-25 |
| NO20061322L (no) | 2006-06-15 |
| PT1667991E (pt) | 2008-07-14 |
| WO2005026150A1 (en) | 2005-03-24 |
| HK1091480A1 (en) | 2007-01-19 |
| CO5690594A2 (es) | 2006-10-31 |
| AR045663A1 (es) | 2005-11-02 |
| DE602004013806D1 (en) | 2008-06-26 |
| ATE395346T1 (de) | 2008-05-15 |
| SI1667991T1 (sl) | 2008-10-31 |
| AU2004272348B2 (en) | 2008-09-04 |
| RU2378268C2 (ru) | 2010-01-10 |
| DK1667991T3 (da) | 2008-08-18 |
| US20090312343A1 (en) | 2009-12-17 |
| CA2538884A1 (en) | 2005-03-24 |
| RU2006112599A (ru) | 2007-11-10 |
| CY1108186T1 (el) | 2014-02-12 |
| JP4795952B2 (ja) | 2011-10-19 |
| MXPA06002964A (es) | 2006-06-14 |
| JP2007505872A (ja) | 2007-03-15 |
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